It is known that the interaction between tumour cells and the extra-cellular matrix, caused or favoured by fibronectin, is inhibited by the intravenous administration of the synthetic pentapeptide Gly-Arg-Gly-Asp-Ser, whose sequence is the same as that of the cell-binding site of fibronectin (Humphries M. J. et al, SCience 233:467,1986).
Ruoslahti and Pierschbacher (Cell 44:517,1986) have proposed the hypothesis that the biological activity of this pentapeptide could be attributed to the tripeptide sequence Arg-Gly-Asp contained in it, without however testing the activity of the latter.
Lam et al (J. Biol. Chem. 262:947,1987) have instead proved that Arg-Gly-Asp is able to bind to some platelet surface glycoproteins, thus suggesting a possible biological action of this tripeptide as an inhibitor of platelet adhesion reactions.
Starting from the knowledge resulting from the above-mentioned state of the art, the applicant has synthesized some tripeptides belonging to the general formula X-Gly-Y, where X is L-Arg or D-Arg and Y is L-Asp or D-Asp, evaluating then their efficacy in experimental tests of antimetastatic activity.
The results have confirmed their efficacy as antimetastatic agents, but have also surprisingly shown their marked immunostimulating activity, not predictable on the basis of the present knowledge.
This immunostimulanting effect has been observed in vitro in experimental murine as well as human models and consists both in a maturation of immature T lymphocytes and in an enhancement of T cell function.
A similar immunostimulating behaviour has been described for the tripeptides Arg-Lys-Glu (U.S. patent application Ser. No. 035,045 of Apr. 6, 1987), Arg-Ala-Arg (U.S. patent application No. 035.044W of Apr. 6, 1987) and Arg-Lys-Asp (European patent application No. 67425 of Dec. 22, 1982).
Moreover, the tripeptides which are the object of the present invention have shown stability in simulated gastric juice: on the basis of what had been observed in the case of the peptides Arg-Lys-Glu and Arg-Ala-Arg, whose stability in simulated gastric ambient was coupled to activity after oral administration to animals, it is possible to attribute to the tripeptides which are the object of the present invention an immunostimulating activity after oral, besides parenteral, administration.
This represents a remarkable advantage in the therapeutical use, with particular reference to children and other patients who do not tolerate the parenteral administration, and also in view of a better patient compliance.
On the basis of what has been above mentioned, these products result to be very userful in the prevention of metastatization in neoplastic patients after surgical removal of the tumour, as well as in the contemporaneous stimulation of the immune system, depressed by both the radiochemotherapic treatments and the operation itself: both these factors are in fact notoriously immunodepressant.
Moreover, the availability of drugs which can be administered by oral route represents, for the therapy of these patients, another undoubted advantage.